3-({60 -substituted amino-{62 -alkoxybenzoxy-propyl)-6,7-or-6,7,8-alkoxy-1,2,3-benzotriazine-4(3h)-ones

ABSTRACT

The present invention pertains to new, pharmacologically valuable basically substituted 1,2,3-benzotriazine-4(3H)-one derivatives having excellent coronary dilator properties and which have the structural formula   WHEREIN R&#39;&#39; is a radical selected from the group consisting of a secondary aliphatic, cycloaliphatic or araliphatic amine containing two to 10 carbon atoms; or of a 5, 6 or 7-membered heterocyclic nitrogen base, which contains in the nucleus in addition to the nitrogen atom a corresponding number of methylene groups as well as an additional member selected from the group consisting of a nitrogen, an oxygen or a sulfur atom, said radical being bound via a nitrogen atom; R1 is an alkoxy group having one to four carbon atoms, which may be in the 6,7 or 6,7,8-position; R2 is an alkoxy group having one to four carbon atoms; m is an integer selected from 1, 2 and 3; and n is an integer selected from 2 and 3; and to processes for producing said derivatives.

United States Patent Beyerle et al.

[ 1 Dec. 19,1972

I54] S-(a-SUBSTITUTED AMINO-B- ALKOXYBENZOXY-PROPYL)-6,7-OR- 6,7,8-ALKOXY-l,2,3-BENZOTRIAZINE- 4(3H)-ONES [22] Filed: May 18, 1970 [21] Appl. No.: 38,544

[30] Foreign Application Priority Data May 22, 1969 Germany ..P 19 26 075.4

[52] US. Cl. ..260/247.2 B, 260/248 AS; 424/248 [51] Int. Cl. ..C07d 87/36 [58] Field of Search ..260/248 AS, 247.2 B

[56] References Cited UNITED STATES PATENTS 3,520,893 7/1970 Beyerle et a! ..260/294.3 3,534,085 10/1970 Narayanan et al. ..260/490 OTHER PUBLICATIONS Gadekar et al.; J. Org. Chem. Vol. 26, Pages 613-15 (1961).

Primary Examiner-Alex Mazel 7 Assistant Examiner-Jose Tovar Attorney-Francis M. Crawford [57] ABSTRACT The present invention pertains to new, pharmacologically valuable basically substituted 1 ,2,3-

I b'enzotriazine-4(3H)-one derivatives having excellent coronary dilator properties and which have the structural formula wherein R is a radical selected from the group consisting of a secondary aliphatic, cycl oaliphatic or araliphatic amine containing two to 10 carbon atoms; or of a 5, 6 or 7-membered heterocyclic nitrogen base, which contains in the nucleus in addition to the nitrogen atom a corresponding number of methylene groups as well as an additional member selected from the group consisting of a nitrogen, an oxygen or a sulfur atom, said radical being bound via a nitrogen atom; R, is an alkoxy group having one to four carbon atoms, which may be in the 6,7 or 6,7,8-position; R is an alkoxy group having one to four carbon atoms; m is an integer selected from 1, 2 and 3; and n is an integer selected from 2 and 3; and to processes for producing said derivatives.

6 Claims, No Drawings wherein R is a radical selected from the group consisting of a secondary aliphatic, cycloaliphatic, araliphatic amine having two to carbon atoms or of a 5, 6 or 7-membered heterocyclic nitrogen base, which contains in the nucleus besides the nitrogen atom a corresponding number of methylene groups as well as a further nitrogen atom, an O or an S atom, said radical being bound via a nitrogen atom,

R stands for lower alkoxy groups having one to four carbon atoms which may be in the 6,7 or 6,7,8" position,

R represent alkoxy having one to four carbon atoms,

m stands for the integers l, 2 or 3 and n means the integers 2 or 3. Furthermore, the present invention relates to processes for the production of said compounds.

The radical of a secondary amine R which is bound via a nitrogen atom may derive in the aliphatic series from mono and diamines, such as dialkylamines, al-

kylalkenylamines, alkylenediamines, hydroxyalkylamines and alkoxyalkylamines.

Such amines are for instance: dimethylamine,

diethylamine, allylmethylamine, methylethylenediamine, N,N-diethyl-N'-methylpropylenediamine, N-methylethanolamine, N-methylpropanolamine, N-isopropylethanolamine, N-butylethanolamine, N-benzylethanolamine, methoxypropylamine, N-methylethoxypropylamine.

Cycloaliphatic amines may be for instance: N- methylcyclopropylamine, N-methylcyclohexylamine.

Amines of the araliphatic series may be for instance:

phenalkylalkylamines such as benzylmethylamine, 5O

binding agent, l,2,3-benzotriazine-4(3H)-one derivatives of the general formula 0 g N-CHQCHCHz--R (R011 i N OH wherein R has the above-given meaning, R is identical with R or, in case R contains an acyloxy radical of the general formula I N-methylsaid R may represent the residue of the underlying hydroxy compound, with an alkoxy benzoic acid of the general formula (Rain-- or a functional derivative thereof, or b. cyclizing substituted o-aminobenzamides of the general formula with nitrous acid.

lf, according to the process described under para a), initial products are used wherein the radical of an amine R, which is bound via a nitrogen atom, contains a hydroxyalkyl group, and if 2 mols of alkoxy benzoic acid or of a functional derivative thereof are employed, one obtains the corresponding diesters. The 3-('yamino-B-hydroxypropyl)-l ,2,3-benzotriazine-4(3H)- ones required as starting material may be obtained by various ways of preparation according to the teachings of the corresponding application having the same title and the same filing date.

The initial products required for the process described under para (b) may be prepared in the usual manner according to known per se processes. The nitrous acid which causes-the cyclization is formed in an acid reaction medium from the alkali metal nitrites employed.

The l,2,3-benzotriazine-4(3H)-one derivatives of the present invention are valuable pharmaceuticals. In particular, they are excellent coronary dilators and, in this respect, superior to other known substances of this kind.

With respect to the change in the oxygen tension in the coronary veinous blood, the pharmacological investigation of the vasodilator action on the coronary vessels was carried out in dogs according to the methods described by W.K.A. Schaper and his co-workers (see W.K.A. SQHAPER, R. XHONNEUX, and J.M. BOGAARD Uber die kontinuierliche Messung des Sauerstoffdruckes im veniisen Coronarblut (Naunyn-Schmiedebergs Arch. exp. Path. u. Pharmak. 245, 383-389 (1963)). The test preparations were applied intravenously to the narcotized and spontaneously breathing animals. On these test conditions the dilatation of the coronary arteries caused by the test substances along with the increase in the coronary blood flow led to an increase in the oxygen tension in.the coronary veinous blood. This oxygen tension was measured according to polarographic methods by means of a platin electrode of the Gleichmann-Liibbers type (see U. GLEICHMANN and D.w. LUEBBERS Die Messung des Sauerstoffdruckes in Gasen und Fliissigkeiten mit der Platin-Elektrode unter besonderer Beriicksichtigung der Messung im Blut, Pfliigers Arch; 271, 431155 (1950) The heart rate was continuously measured by electronic methods from systolic peaks of the arterial blood-pressure. The arterial 38.0 g. (0.1 mol) 3-(-y-morpholino-p hydroxy-propyl)- 6,7,8-trimethoxy-l ,2,3 -ben'zotriazine-4( 31-! )-one dissolved in 250 c.c. anhydrous benzene and 11.1 g. (0.11mol) triethylamine are added. Subsequently, a

blood pressure was measured n the known manner in 5 1 solution of 25.3 g. (0.11 mol) 3,4,5-tnmethoxybenzoyl the femoral artery with the aid of an electromanometer chloride in 100 c.c. anhydrous benzene are added of the Statham-straln-gauge type. dropwlse whlle stirring at room temperature during 30 The following table gives the results of the pharminutes and stirring is continued for 2 hours atroom macologlcal investigations which were carried through. temperature. The reaction mixture is then stirred for The preparations werev tested in the form. of their another 6 hours under reflux and sucked off, while hot, respective hydrochlondes: from the trlethylamine hydrochloride being Maximal increase in Maximal change in 1 oxygen tension in the blood pressure LD 50, the coronary vein- Maximal change in (systolic/diastolic) gJkg. Dosage, ous blood lnthe heart rate ininmouse mgJkg. 7 Preparation i.v. i.v. Percent Minutes Percent Minutes Percent Minutes 3-h-morpho1ino-fl-(3,4,5-trimethoxybenzoxy)-propy1]-6,7,8-trimethoxy-l,2,3-benzotriazine-4(3H)-one 0.2 0.5 +106 25 19 25 ""*3/ 32 25 3-['y-(4-fi-3,4,' -trimethoxybenzoxyethylpiperazino)-B-(3,4,5-

trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-l,2,3-benzo-' n 1 triaziue-4(3H)-one-.. 0.25 0.5 +109 60 20 -22/--31 60 3-l'y-morphollno-fl-(3,B-dimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-l,2,3-benzotrlazinc-4(31I)-0nc 0. 0.6 +57 15 +23 15 25l19 115 3-[v-morphollno-fl-(S,5-dilnethoxy4-n-butoxybcllzoxy)-propyl]- 6,7,8-trimethoxy-1,2,3-benzotriazlnc-4(31I)-one 0.4 0.5 +55 40 '-10 40 32/ 25 35 3-l'y-1iiD6l'1dii10-fl-(3' 4,5-trirnethoxybcnzox y) propyl]-6,7,8-

trimcthoxy-l,2,3-benzotriazine-4((311)-one 0.1 0.5 +25 35 -5 35 +6l-12 15 3-[v-hexamethyleneimino-fl-(3,4,5-trimethoxybenzoxy)-propy1]- Y I 6,7,8-trlmethoxy-1,2,3-bcnzotrlazine-4(311)-one 0.13 0.5 +10 12 30 4/--18 20 3-[ -(4'-methylpiperazlno)-fi-(3,4,5-trimethoxybenzoxy)-propyl]- 0,7 B-trlmethoxy-l,2,3-bcnzotriazine-4 (311)-0110 0. 24 2.0 +65 65 -5 65 7/-14 15 3-[ 4-phenylpiperazino)-fl-(3,4,5-trimethoxybenzoxy)-propyl]- 6,7,8-trlrnethoxy-1,2,3-benzotriazine-4 (BID-one 0.25 0.5 +17 15 -3 15 4/--6 15 S-I-Y-pynOIidino-B-(3,4,5-trimethoxybenzoxy)-propyl]-6,

trimethoxy-l,2 3-benzotriazine-4(3H)-one 0. 043 0.5 +79 80 11 80 .-.|=0 3-[ -(N-methyl- 'y-methoxypropylamino)B-(3,4,5-trimethoxybenzoxy)-propyi]-6,7,8-trimethoxy-1,2,3-bcnzotriazine-4(3II)- one .05 +138 240 13 '-35/36 35 3[-y- (N -methyl-N-'y-d1ethylarn.inopropylamino) -B-(3 ,4,5-tri methoxybenzoxy)-propy1]-6,7,8trimethoxy-1,2,3-benzotriazine- 4(3H)-one 0.028 2.0 +267 155 -15 166 --51/48 155 3-[7-(N-methy1-N-benzylarmno)-B-(3,4,5-tnmethoxybenzoxy)- propyil-6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)-o11e For a better understanding of the nature and the obprecipitated. The filtrate is washed with water, with a' jects of this invention, reference should be made to the accompanying examples which are of an illustrative rather than a limiting nature. Unless otherwise stated, all temperatures given are in degrees Centigrade.

10 percent aqueous sodium bicarbonate solution and again with water and finally dried 'over anhydroussodium sulfate. Subsequently, the solvent is distilled off at 50 in the water-jet vacuum. The residue, a colorless crystal powder, is triturated with little ethyl acetate and Example I sucked off. By recrystallization from ethyl acetate one o obtains the 3-[y-morpholino-B-(3,4,5-trimethox- & ybenzoxy)-propyl ]-6,7,8-trimethoxy-l ,2,3- R-cHr-cH-cm-N b benzotriazine-4(3H)-one in the form of colorless t crystals having a melting point of 142-144. Yield: 48 fl 11:0 g. 84 percent of the theoretical) OCH; I

C1130 -OCH3 .Example 2 i L CH3 v 0 com Mil -K ?\l-C1Il-ClICHr-N N--cH.--cm-o-co- 0cm l l (tum (Eon.

are

benzotriazine-4(3l-l)-one dihydrochloride are dissolved in 500 c.c. anhydrous chloroform with the addition of water-jet vacuum and the residue, a colorless oil, is dissolved in anhydrous ether. By the addition of etheric hydrochloric acid until congo paper turns blue one obtains the dihydrochloride of the 3- 4'p 3,4,s-

40.4 g. (0.4 mol) triethylamine. A solution of 46 g. (0.2 5 trimethoxy-benzoxyethylpiperazino[ l '])-fi-3,4,5- mol) 3,4,S-trimethoxybenzoyl chloride in 150 c.c. antrimethoxybenzoxy-propyl]-6,7,8-trirnethoxy-l,2,3- hydrous chloroform is added dropwise while stirring benzotriazine-4(3l-l)-one in the form of colorless within 1 hour. After the decay of the exothermic reaccrystals decomposing at 150. Yield: 70 g. 79 pertion stirring is continued for another 2 hours at 40- 50 cent of the theoretical) The thusly obtained reaction mixture is first washed Analogously to the description given in Examples 1 several times with water, then with a percent aqueand 2 the following. compounds f th present i ous sodium bicarbonate solution and again with water. tion may be prepared: Subsequently, the solvent is distilled off at 40 in the General formula: water-jet vacuum and the residue, a light yellow oil, is 0 dissolved, for further purification'purposes, in dilute aqueous hydrochloric acid. This solution is extracted with ether and filtered in order to become limpid. By (Rl)n l the addition of potassium carbonate until the reaction y 4 mixture shows an alkaline reaction (pl-l 9), the diester being formed separates in the form of a colorless oil. It is extracted with ethyl acetate which is washed several (mm times with water and dried over anhydrous sodium I sulfate. The solvent is then distilled off at in the Melting point degrees (hydroih (B2)) R chloride) e,1,s oorn i mm 125 Q -oc OCHs Same as above ?CH; Same as above.

-oc-ocrm OCH:

D0 (|)C7H5 -N (CzHs) z; 200'202 -0o-0cm OCzHs D0 OCH; Same as above 8- -00 -QCH:

OCH:

Do Same as above O 190 D0 .d0 Same as above 7 Do -410 -N NCHs D a ms 0 do -N BP-CtHs I Do do N so VM J,

OH: do I ICH=-CH:CHzOCHs -75 Do -1 r-cH,-0Hr-cH,N(0,Ht)1

Do do i 75 -N--CHg-COHs on Do .do a 85 Melting point degrees (hydro- (R1)n (R011; R chloride) Do do 85 CH /CH: D; d0 a NCH H2 6,7,-(OCH3)2 do 136-138 Same as above do N D0 ..do 41mins), 195 Do .410 on: 180

NCH CH= 0H,

Do -.do (I311; 165

V NCH2-CH7C H1N (C2Hs)2 150.--. do v 0on3 192 N lb-CHr-CHgOOC O CHa Dihydrochloride. i v v Example 3 hydrochloric acid. The aqueous hydrochloric acid solu- 2- nitro-3 ,4,5-trimethoxy-N-(-y-diethylamino-flhydroxypropyl)-benzamide 82.6 g. (0.3 mol) 2-nitro-3,4,5-trimethoxybenzoyl chloride are dissolved in 200 c.c. anhydrous benzene and added dropwise, while stirring, to a solution consisting of 43.8 g. (0.3 mol) -y-diethylamino-B-hydroxypropylamine and 30.3 g. (0.3 mol) triethylamine in 500 c.c. anhydrous benzene. Stirring is continued for 3 hoursunder reflux and after cooling down, the filtrate is evaporated to dryness in vacuo. For further purification purposes the crude product is dissolved in dilute hydrochloric acid and, after filtration, the filtrate is rendered alkaline by the addition of an aqueous potassium carbonate solution. The base which hereby separates in the form of an oil, is dissolved in ethyl acetate and washed several times with water. After drying over potassium carbonate the ethyl acetate solution is concentrated in vacuo and thus obtained is the 2- nitro-3,4,5-trimethoxy-N-('y-diethylamino-B-hydroxypropyl)-benzamide in the form of a yellowish oil. Yield: 91 g. -(79 percent of the theoretical) 2-nitro-3 ,4,5 -trimethoxy-N-['y-diethylamino-B-( 3 ,4,5 trimethoxybenzoxy)-propyl]-benzamide 38.5 g. (0.1 mol) 2-nitro-3,4,5-trimethoxy-N-('ydiethylamino-B-hydroxypropyl)-benzamide and 15.15 g. (0.15 mol) triethylamine are dissolved in 200 c.c. anhydrous benzene and admixed with stirring with a solution consisting'of 34.5 g. (0.15 mol) 3,4,5-trimethoxybenzoyl chloride in 150 c.c. anhydrous benzene. Subsequently, the reaction mixture is heated to the boil and stirring is continued for 6 hours under reflux. After cooling down the reaction product is stirred out with 300 c.c. water and the benzene layer is separated. Subsequently, the benzene layer is shaken out with dilute tion is rendered alkaline by the addition of aqueous potassium carbonate solution and the base which separates in the form of an oil is dissolved in ethyl acetate. The thusly obtained ethyl acetate solution is washed with water and evaporated to dryness, after drying over potassium carbonate, in vacuo. For further purification the crude product is recrystallized from alcohol. Thus obtained is the 2 -nitro-3,4,5-trimethoxy- N-[y-diethylamino-B-(Ii,4,5-trimethoxybenzoxy)- propyl]-benzamide in the form of light yellow crystals melting at 107. Yield: 46 g. 79.5 percent of the theoretical) 2-amino-3,4,5trimethoxy-N-['y-diethylamino-B-( 3,4,5-trimethoxybenzoxy)-propyl]-benzamide of etheric hydrochloric acid the dihydrochloride of the I 2-amino-3,4,5-trimethoxy-N-[y-diethylarnino-fli3,4,5 TRIMETHOXYBENZOXY )-propyl]-benzamide precipitated in the form of colorless needles having a decomposition point of Yield: 49 g. 78.7 percent of the theoretical) 3 [7diethylamino-B-( 3 ,4 ,5 -trim ethoxybenzoxy )-propyl ]-6,7,8-trimethoxy-l ,2,3 -benzotriazine-4( 3H )-one 31 g. (0.05 mol) 2-amino-3,4,5-trimethoxy-N-['ydiethylamino-B-(3,4,5-trimethoxybenzoxy)-propyl1- benzamide-dihydrochloride are dissolved in c.c.

water and at -5 admixeddropwise while stirring and cooling with a solution consisting of 3.5 g. (0.05 mol) sodium nitrite in 20 c.c. water. Stirring is continued for 2 hours at 0-5, then the temperature is allowed to reach room temperature. After having stirred overnight, the reaction mixture is rendered neutral by the addition of aqueous sodium bicarbonate solution and the reaction product that precipitates in the form of crystals is sucked off. For further purification purposes it is then recrystallized from methanol. Thus obtained is the 3-[7-diethylamino-B-( 3 ,4,5-trimethoxybenzoxy)- propyl ]-6,7,8-trimethoxy-l ,2,3-benzotriazine-4(3l-l one in the form of colorless needles melting at 92-95. Yield: 22 g. =(78.6 percent of the theoretical) What is claimed is:

l. A compound of the formula wherein R is a radical selected from the group consisting of morpholino, piperidino, pyrrolidino and hexamethylene-imino; R, is a lower alkoxy group having one to four carbon atoms attached to positions 6,7, or

6,7,8; R, is an alkoxy group having one to four carbon benzoxy)-propyl]-6,7,8-trimethoxy-l,2,3-

benzotriazine-4(3H)-one, or the pharmaceutically acceptable salts thereof.

5. 3-[-y-hexamethylene-imino-B-(3,4,S-trimethoxybenzoxy )-propyl ]-6,7 ,S-trimethoxy-l ,2 ,3-

' benzotriazine-4(3H)-one, or the pharmaceutically acceptable salts thereof.

6. 3-[-y-pyrrolidino-fl-(3,4,5-trimethoxybenzoxy)- propyl ]-6,7,8-'trimethoxy -l ,2,3 -benzotriazin e-4( 3 H one, or the pharmaceutically acceptable salts thereof. 

2. 3-( gamma -morpholino- Beta -(3,4,5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-1,2,3-benzotriazine -4(3H)-one and pharmaceutically acceptable salts thereof.
 3. 3-( gamma -morpholino- Beta -(3,5-dimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H) -one, or the pharmaceutically acceptable salts thereof.
 4. 3-( gamma -morpholino- Beta -(3,5-dimethoxy-4-n-butoxy-benzoxy)-propyl) -6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)-one, or the pharmaceutically acceptable salts thereof.
 5. 3-( gamma -hexamethylene-imino- Beta -(3,4,5-trimethoxy-benzoxy)-propyl) -6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)-one, or the pharmaceutically acceptable salts thereof.
 6. 3-( gamma -pyrrolidino- Beta -(3,4,5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-1,2,3-benzotriazine -4(3H)-one, or the pharmaceutically acceptable salts thereof. 